Is CACNB2 p.Val421Ile (c.1261G>A) pathogenic?

CACNB2 p.Val421Ile (c.1261G>A) is classified Uncertain significance in CACNB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.5327); Very rare (popmax 0.00225%, eas); Associated with Brugada syndrome 4.

What condition is associated with CACNB2 p.Val421Ile (c.1261G>A)?

CACNB2 p.Val421Ile (c.1261G>A) is associated with Brugada syndrome 4 (ClinVar).

How common is CACNB2 p.Val421Ile (c.1261G>A) in the general population?

CACNB2 p.Val421Ile (c.1261G>A) is very rare (popmax 0.00225%, eas) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CACNB2 p.Val421Ile (c.1261G>A)?

AlphaMissense predicts ambiguous (score 0.5327) — an in-silico prediction, not a clinical call.

CACNB2 p.Val421Ile

c.1261G>A · rs745337273 · VCV299561

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Conditions

Brugada syndrome 4

Computational evidence

Protein change
AlphaMissense	0.5327	ambiguous
REVEL	0.35	indeterminate
SaProt	LLR -9.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,404 alleles

Overall 0.000125% 2/1,605,888 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,404
European (non-Finnish)	8.51e-05%	1,175,621

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CACNB2
Protein: p.Val421Ile
Coding: c.1261G>A
MANE Select: NM_201596
dbSNP: rs745337273
Type: single nucleotide variant
Location: chr10:18536155 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 421: an α-helix

Full CACNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Brugada syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CACNB2 p.Val421= Likely benign ★ same residue
CACNB2 c.1206+5G>A Uncertain significance ★★ same condition
CACNB2 c.1303-3C>T Uncertain significance ★★ same condition
CACNB2 c.1488+6G>A Uncertain significance ★★ same condition
CACNB2 p.Ala105Thr Uncertain significance ★★ ⚠ same condition
CACNB2 p.Ala118Val Uncertain significance ★★ ⚠ same condition
CACNB2 p.Ala128Val Uncertain significance ★★ ⚠ same condition
CACNB2 p.Ala139Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cacnb2-p-val421ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown